臺灣博碩士論文加值系統

中文摘要

Cytochrome P450 1B1 （CYP1B1）是一種含有heme血素的單氧氧化?，在細胞內會代謝多種多環芳烴與芳香胺類化合物以及參與視黃酸與固醇類荷爾蒙的代謝。在哺乳動物體內，2.3.7.8-四氯二聯苯戴奧辛會透過AHR/ARNT細胞接受器的活化作用誘發CYP1B1基因在多種組織內的表現。在人類，CYP1B1基因亦參與了大腸直腸細胞與肺腺細胞癌化機轉以及先天性青光眼的遺傳性病變機制。我們在斑馬魚中找到與哺乳動物CYP1B1基因有高度相似性的基因。在胚胎孵化之前，斑馬魚CYP1B1基因專一性表現在中後腦中隔、間腦以及眼睛等部位。2.3.7.8-四氯二聯苯戴奧辛（TCDD）的處理並不會對這些部位原生性CYP1B1 mRNA的表現有明顯的影響，但是會在鰓弧、前腸以及心臟等部位誘發出新的CYP1B1 mRNA表現。利用反意morpholino寡核酸將胚胎內的AHR2基因弱化會抑制戴奧辛在鰓弧等處所誘發的CYP1B1 mRNA表現，但是對於眼睛等部位的原生性CYP1B1表現則不造成影響，顯示戴奧辛在鰓弧所引起的誘發性CYP1B1基因表現與正常胚胎在眼睛等部位的原生性CYP1B1表現是由不同的基因調控機制所控制。將CYP1B1基因弱化，並不會改變2.3.7.8-四氯二聯苯戴奧辛所造成的頭骨變形與心包膜膨大等生理毒性反應，顯示CYP1B1基因並未參與戴奧辛的毒性機轉。
CYP1C是魚類中CYP1新的次家族，在胚胎及成魚中基本表現在許多組織。就像其他CYP1家族成員，CYP1C可以被多環芳香碳氫化合物誘導產生基因表現。先前從斑馬魚胚胎中得到CYP1C1 cDNA （GenBank accession number AY_928186）。在late pharyngula時期斑馬魚CYP1C1開始基本表現在主動脈弧（aortic arches），在48-72小時間，有較高的原生性基因表現活性，接著表現逐漸減弱，TCDD曝露下CYP1C1的基因表現則明顯增強。雖然CYP1A1和CYP1C1均在胚胎血管中表現，但兩者表現形式各有不同，其中CYP1A1會表現在全身血管組織中而CYP1C1的表現則僅局限在主動脈弧的血管組織中，兩者對血管部位的選擇差異性有待未來進一步探討。
最後，為了探討斑馬魚內三種不同AHR對CYP1基因表現的功能，分別以反意morpholino弱化各AHR的轉譯後，探討各CYP1基因的表現情況。在CYP1C1基因方面，弱化AHR1A、AHR1B對CYP1C1基因表現僅引起輕微的影響，而弱化AHR2則完全抑制了原生性及TCDD所誘導產生的CYP1C1基因表現，顯示AHR2在CYP1C1基因表現中扮演重要的角色。在CYP1A1方面，弱化AHR1A轉譯後對CYP1A1並無明顯影響，而弱化AHR1B會降低血管部位原生性以及TCDD所誘導產生的CYP1A1表現，但仍維持眼睛部位的原生性CYP1A1基因表現。弱化AHR2則會完全抑制眼睛以外其他部位的原生性以及TCDD所誘導產生的CYP1A1基因表現。在CYP1B1方面，弱化AHR1A轉譯並不會對CYP1B1的表現產生影響，但是弱化AHR2則會明顯減弱但並未完全抑制眼睛部位的原生性CYP1B1表現，且可完全抑制TCDD所誘導之CYP1B1表現能力，顯示AHR2對原生性CYP1B1基因的表現相當重要，而對TCDD所誘導的CYP1B1基因表現能力則扮演不可或缺的功能。整體而言，雖然班馬魚中具有多種的AHR，但是其中僅有AHR2對調控CYP1的三種基因均扮演了關鍵性的角色。

Abstract

Cytochrome P450 1B1 （CYP1B1） is a heme-containing monooxygenase that metabolizes various polycyclic aromatic hydrocarbons （PAHs） and arylamines, as well as retinoic acid and steroid hormones. Here we presented that zebrafish CYP1B1 is constitutively expressed in embryonic ocular cells, diencephalons, and midbrain-hindbrain boundary during pharyngula stage. After hatching, the constitutive-type of CYP1B1 transcription is attenuated. TCDD exposure elicited de novo CYP1B1 transcription in pharyngeal arches and heart tissues at larval stage. Knockdown of AHR2 in zebrafish embryos abolished the induction of CYP1B1 by TCDD, but did not eliminate the basal level of CYP1B1 transcription in ocular cells. It suggests that the constitutive and TCDD-inducible types of CYP1B1 transcriptions are modulated by distinct pathways and exhibits different tissue specificity. We have also investigated the role of CYP1B1 in TCDD-mediated embryonic toxicity. Here we presented that CYP1B1 knockdown did not prevent TCDD-induced pericardial edema and cranial defects, suggesting that CYP1B1 does not involve in the developmental toxicity of dioxin.
CYP1C is a novel CYP1 subfamily that is constitutively expressed in a broad range of adult fish tissues and developing embryos. Like other CYP1 members, CYP1C genes can be induced by various polycyclic aromatic hydrocarbons. However, the pattern of CYP1C expression during early stages of development has not been fully addressed. Previously, we have cloned a complete CYP1C1 cDNA from zebrafish embryo （GenBank accession number AY_928186）. Here we reported that zebrafish CYP1C1 exhibited a restricted expression pattern dominantly in the vasculature of the aortic arches at late pharyngula stage. This basal type of transcription reached highest level at 48-72 hpf and subsequently its expression attenuated gradually. TCDD exposure elicited a high level of CYP1C1 transcription.
The function of AHR1A, AHR1B and AHR2 on CYP1 tanscription has also been investigated. Blocking AHR1A only had mild effects on TCDD-induced CYP1A1 and CYP1C1 transcription, but had no significant effect on CYP1B1 transcription. Knockdown AHR1B reduced both constitutive-type and TCDD-induced CYP1A1 transcription, but did not change CYP1C1 expression. Blocking AHR2 could completely inhibite TCDD-induced CYP1A1, CYP1B1 and CYP1C1 transcriptions and also reduced significant level of their constitute-type transcriptions in non-ocular tissues.

目錄
謝誌-------------------------------------------------------I
中文摘要 II
英文摘要 V
目錄 VII
壹、前言 1
一、Cytochrome P450 superfamily 1
二、芳香烴碳氫化合物接受器(aryl hydrocarbon receptor,AHR) 4
1、AHR訊息傳遞系統 7
2、AHR訊息傳遞負調控機制 11
三、戴奧辛 (2,3,7,8-tetrachlorodibenzo-p-dioxin, TCDD) 12
四、肝臟外之CYPs 14
五、研究動機 17
貳、實驗材料與方法 18
一、實驗材料-------------------------------------------- 18
A、菌種及質體DNA 18
B、藥品---- 18
C、酵素及試劑 19
二、實驗方法--------------------------------------------- 21
A、斑馬魚飼養與受精胚胎收集--------------------------- 21
B、快速放大cDNA末端聚合?連鎖反應 22
C、DNA洋菜膠電泳--------------------------------------- 26
D、DNA分子之萃取--------------------------------------- 26
E、DNA接合反應----------------------------------------- 27
F、質體轉型 28
G、反轉錄聚合?連鎖反應-------------------------------- 28
H、RNA全覆式原位雜交-----------------------------------29
參、實 驗 結 果 33
一、 CYP1B1部分------------------------------------------ 33
1、CYP1B1基因選殖------------------------------------- 33
2、CYP1B1在斑馬魚胚胎的表現--------------------------- 33
3、TCDD誘發CYP1B1基因表現 34
4、CYP1B1基因表現的調節作用--------------------------- 35
5、CYP1B1之弱化無法清除TCDD所誘發的生理毒性----------- 36
二、CYP1C1部分-------------------------------------------- 36
1、CYP1C1在斑馬魚胚胎的表現----------------------------36
2、TCDD對CYP1C1基因表現量的影響------------------------37
3、AHR1A、AHR1B及AHR2在調節CYP1C1基因表現中所扮演的角色 37
4、AHR1A、AHR1B及AHR2在調節CYP1A基因表現中所扮演的角色 38
肆、實 驗 討 論 40
一、 CYP1B1部分 40
1、斑馬魚CYP1B1序列比對 40
2、種CYP1B1基因表現形式 41
3、孵化前CYP1B1基因的表現 41
4、孵化後經由AHR2的路徑誘發CYP1B1基因表現 42
5、CYP1B1未參與TCDD的毒性機轉 42
二、CYP1C1部分--------------------------------------------43
1、各CYP1基因表現的比較-------------------------------43
2、TCDD誘發CYP1基因表現的機制 44
3、斑馬魚各AHR基因弱化對胚胎時期CYP1基因家族的影響---44
伍、參考文獻--------------------------------------------- 46
陸、圖表------------------------------------------------- 60
表1、人類的CYP1A2、 CYP1B1和斑馬魚的CYP1B1在受質辨識
序列上胺基酸的比對
表2、斑馬魚各AHR基因弱化對胚胎時期CYP1基因家族的影響
Figure 1、 斑馬魚CYP1B1與其他動物CYP1B1序列比對
Figure 2、 斑馬魚正常胚胎在發育時期原生性及TCDD誘發型CYP1B1表現
形式
Figure 3、 ahr2反意寡核酸（ahr2 morpholino）有效抑制AHR2的轉譯作用
Figure 4、 弱化AHR2可以完全抑制TCDD所誘發CYP1B1的表現，但無法
完全抑制原生性CYP1B1的表現
Figure 5、 使CYP1B1弱化（knockdown）無法阻止TCDD所誘發的生理毒害
Figure 6、 斑馬魚正常胚胎在發育時期原生性及TCDD所誘發CYP1C1的表現形式
Figure 7、 將AHR1A弱化後，觀察原生性CYP1C1的表現
Figure 8、 AHR1A弱化後，由TCDD所誘發的CYP1C1基因表現僅受到輕微的影響
Figure 9. AHR1B弱化，在96小時的斑馬魚胚胎中原生性CYP1C1表現增加
Figure 10. 將AHR1B弱化，由TCDD所誘發的CYP1C1表現沒有明顯抑制
Figure 11. AHR2弱化後的斑馬魚胚胎，幾乎完全抑制CYP1C1的原生性表現
Figure 12. 將AHR2弱化，幾乎完全抑制TCDD所誘發CYP1C1的基因表現
Figure 13. 將AHR1A弱化，觀察原生性CYP1A1的表現
Figure 14. 將AHR1A弱化，由TCDD所誘發的CYP1A1表現有些微的影響
Figure 15. AHR1B弱化後，原生性CYP1A1的表現明顯減弱
Figure 16. AHR1B弱化，TCDD所誘發的CYP1A1表現減少
Figure 17. 將AHR2弱化，除了眼睛外，幾乎完全抑制原生性CYP1A1的表現能力
Figure 18. 將AHR2弱化，除了眼睛外，幾乎完全抑制TCDD所誘發的CYP1A1表現
Figure 19. 將AHR1A弱化，並未影響原生性CYP1B1或TCDD所誘發的CYP1B1表現
Figure 20. 比較斑馬魚AHR1A弱化對胚胎發育時期CYP1基因家族的影響
Figure 21. 比較斑馬魚AHR1B弱化對胚胎發育時期CYP1基因家族的影響
Figure 22. 比較斑馬魚AHR2弱化對胚胎發育時期CYP1基因家族的影響

附件-----------------------------------------------------84
Influence of TCDD on Zebrafish CYP1B1Transcription during Development

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